The long-term goal of this project is to provide information useful in predicting conditions in which non-target vertebrates may be unusually susceptible (or resistant) to the toxic action of pesticides, or of other chemicals as a result of exposure to pesticides. This will be accomplished by research directed at identifying, measuring and modifying the dynamic relationships among critical biochemical pathways of metabolism and action in relation to the response of intact organisms. In the proposed research, emphasis is placed on studies of interactions involving organophosphorus (OP) pesticides, primarily phosphorothionate insecticides. Two general questions will be investigated in rodents: What is the significance of carboxylesterase inhibition by OP insecticides in modulating the action and metabolism of other pesticides and non-pesticidal organic esters? and, How does the metabolic control of phosphorothionate insecticide toxicity differ when exposure is by oral, dermal or inhalation routes? The latter question is particularly important for understanding and predicting the consequences of occupational exposure to pesticides. It will be addressed by in vivo and in vitro studies of target and biotransformation enzyme interactions with organophosphates in liver, skin and lungs. These studies will be coupled with disposition kinetics and dose-response relationships in intact animals that are exposed by different routes to representative OP insecticides under standardized conditions.